Abstract 1875: A novel T-cell-engaging therapeutical antibody against GPRC5D&amp;BCMA for multiple myeloma treatment
Authors: Feng Li, Guojin Wu, Hao Peng, Jiangmei Li, Yue Qi, Guangzhong Lin, Huifang Liu, Wenqi Hu, Jinying Ning
Journal: Cancer Research (2023)

Abstract T-cell-engaging therapeutical antibodies, such as Talquetamab (targeting GPRC5D and CD3 with 1:1 formation) and CC-93269(targeting BCMA and CD3 with 2:1 formation) have shown promise in multiple myeloma (MM) treatment. However, MM usually had heterogeneous cell populations with independent expressions of BCMA and GPRC5D, so TCEs only targeting BCMA or GPRC5D are suspected to have limitation on anti-tumor effect. Development a TCE simultaneously binding BCMA and GPRC5D may extend its therapeutic efficacy. MBS314 is a humanized tri-specific antibody against GPRC5D, BCMA, and CD3 for r/r MM treatment. MBS314 has a weaker binding to CD3 (KD=181nM) than Talquetamab (KD=25.6 nM) and CC-93269 (KD=41.0 nM). Meanwhile,it has high affinities to GPRC5D (KD=3.5nM) and BCMA (KD=0.22nM), similar to Talquetamab (KD=4.21 nM, to GPRC5D) and CC-93269 (KD=1.0 nM, to BCMA). We developed a reporter assay to evaluate the function of TCEs: co-culture the tumor cells, such as H929, AMO1, or KMS-11, with Jurkat-NFAT-Luc reporter cells can induce luciferase expression, which can reflect the CD3 agonist signaling. MBS314 stimulated CD3 signaling when the reporter cells cultured along with any of the above MM cells, while Talquetamab failed to stimulate CD3 signaling when the reporter cells cultured along with KMS-11, which has low expression of GPRC5D, and CC-93269 was unable to stimulate CD3 signaling with AMO1 which has low expression of BCMA. The cytotoxicity assay also indicated MBS314 mediated T cell killing any of the above cells, while Talquetamab failed to kill KMS-11 and CC-93269 killed AMO-1 with low efficiency. In our in vivo xenograft MM murine models, MBS314 and Talquetamab induced regression of established MM.1S tumor in all of the mice (4/4), while CC-93269 induced regression in half of the mice (2/4) with dose at 0.5mg/kg injected twice a week. And MBS314 inhibited the growth of the MOLP8 tumor, while Talquetamab and CC-93269 failed to prevent MOLP8 tumor growth. Especially, our ex vivo cytotoxicity assay with bone marrow mononuclear cells (BM-MNCs) from 15 MM patients indicated that MBS314 more efficiently induced T-cell-mediated depletion of CD138+ MM cells than Talquetamab (mean(EC50)=0.06nM vs.1nM) and CC-93269 (mean(EC50)= 0.06nM vs.0.33nM). In addition, owning to the low affinity to CD3, MBS314 has no detectable toxicity in CD3 humanized mice. In summary, our data show MBS314 is a promising TCE for MM treatment with high efficacy and broad spectrum targeting both GPRC5D and BCMA, and also has excellent safety with low CD3 binding affinity. Citation Format: Feng Li, Guojin Wu, Hao Peng, Jiangmei Li, Yue Qi, Guangzhong Lin, Huifang Liu, Wenqi Hu, Jinying Ning. A novel T-cell-engaging therapeutical antibody against GPRC5D&amp;BCMA for multiple myeloma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1875.